DESCRIPTION (Applicant's Abstract): The candidate proposes to undertake a program of research which will involve extensive training in the fields of electrophysiology and synaptic plasticity. The addition of expertise in these fields will complement the candidate's already extensive background in the molecular biology and biochemistry of synaptic vesicle function. Specifically, the goals of the research are to understand the basis of long-term potentiation (LTP) in the mossy fiber synapses of the hippocampus, an area that relies on presynaptic mechanisms for this plasticity. Two proteins, rab3a and protein kinase A (PKA), whose essential role at mossy fiber LTP (mfLTP) has already been established will be the focus of investigation. To determine the downstream effectors of rab3a which mediate mfLTP, extensive electrophysiologic analysis of a null mouse strain for the candidate rab3a effector protein, rim, will be undertaken. Once the basis of the rim (-/-) mutant phenotype on mfLTP is characterized, rescue experiments in primary cultures of hippocampal granule cells using transient expression systems will be performed. This approach will further be used to identify the specific domains of rim required for mfLTP. A second line of study will be the pursuit of targets of PKA phosphorylation required to establish mfLTP. In addition to standard techniques of studying phosphoproteins, a specific analysis of proteins important for synaptic vesicle docking and fusion will be performed as there is evidence that suggests they may be targets of PKA. The final area of investigation will return to the role of rim in mfLTP and seek to understand the molecular basis of this effect by identifying interacting proteins. In the long term, using such approaches to study synaptic plasticity, the candidate hopes to understand the role of plasticity in memory, recovery from brain injuries such as stroke, and neurodegenerative diseases such as Alzheimer's with the goal of improving therapy in disease states. The candidate's background of graduate study in Neuroscience and residency training in Neurology is particularly suited to make basic science discoveries and apply them to areas of clinical relevance. The mentor, Dr. Robert Malenka is also a physician-scientist and serves as an ideal role model for excellence in research. The research environment at Stanford University School of Medicine is well suited both in its physical plant and intellectual resources to embark upon these studies. Lastly, in addition to acquiring new research skills, the candidate will be active in a variety of relevant scientific meetings (journal clubs, lecture series, national meetings) and the Department of Neurology to prepare for a career in academic medicine with both research and clinical responsibilities.